JAMA
August 31, 2023
Charles L. Raison, Gerard Sanacora, Joshua Woolley et al.
493 citations
A single 25-mg dose of synthetic psilocybin, administered with psychological support, produced a clinically significant and sustained reduction in depressive symptoms and functional disability over 43 days in adults with major depressive disorder. In a phase 2 trial of 104 participants, those receiving psilocybin showed a mean 12.3-point greater improvement on the Montgomery-Asberg Depression Rating Scale at day 43 compared with those receiving a niacin placebo. Psilocybin also improved daily functioning and led to more sustained response, though not remission. No serious adverse events occurred, but psilocybin was associated with more overall and severe adverse events.
Psychiatry Research
January 2, 2020
Simon B. Goldberg, Brian T. Pace, Christopher R. Nicholas et al.
234 citations
A meta-analysis of four studies (three randomized, placebo-controlled; one uncontrolled) with 117 participants found that psilocybin combined with behavioral interventions produced large reductions in anxiety and depression among people with elevated symptoms. Within-group effects from before treatment to after treatment and at follow-up were large (Hedges' g = 1.16 to 1.47) and statistically significant. Across the placebo-controlled studies, the pre-post effects compared to placebo were also large (g = 0.82 to 0.83) and statistically significant. No serious adverse events were reported. The results tentatively support further research on psilocybin for anxiety and depression, though the small number of studies and potential bias limit confidence.
Clinical Pharmacokinetics
March 28, 2017
Randall Brown, Christopher R. Nicholas, Nicholas V. Cozzi et al.
189 citations
Psilocybin is a psychedelic tryptamine being studied for depression and substance use disorders. In an open-label study of 12 healthy adults, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg were given at monthly intervals. No psilocybin was found in plasma or urine; its active metabolite psilocin had an elimination half-life of 3 hours (standard deviation 1.1). Renal clearance of intact psilocin accounted for less than 2% of total clearance, indicating no dose reduction is needed for mild-moderate renal impairment. Body weight did not predict variation in psilocin clearance. No serious adverse events occurred. A fixed 25 mg dose approximates the exposure of a 0.3 mg/kg dose.
Journal of Psychopharmacology
June 27, 2018
Christopher R. Nicholas, Kelsey M. Henriquez, Michele Gassman et al.
85 citations
Healthy participants given escalating doses of psilocybin (0.3, 0.45, and 0.6 mg/kg) showed a significant linear dose-related increase in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of complete mystical experiences. Dose 3 produced significantly higher transcendence of time and space scores than dose 1, while no dose-related differences emerged for total scores or mystical experience rate. Positive persisting effects 30 days after the last dose were significantly higher than negative ones, and a moderate increase in well-being or life satisfaction was associated with the maximum mystical experience score. Pharmacokinetic measures correlated with dose but not with mystical experience scores or rate, indicating that a complete mystical experience was not necessary for positive outcomes.
Clinical Pharmacology in Drug Development
April 6, 2020
Elyes Dahmane, Paul R. Hutson, Jogarao Gobburu
44 citations
Psilocybin, a compound being developed for major depressive disorder, is converted to psilocin after absorption. A single ascending dose study (0.3 to 0.6 mg/kg) found a significant but shallow relationship between psilocin concentration and QTc interval prolongation. At a clinical dose of 25 mg, the mean peak psilocin concentration is 18.7 ng/mL, associated with a mean QTcF change of 2.1 milliseconds (upper 90% confidence interval: 6.6 ms). The upper confidence limit crossed 10 ms at 31.1 ng/mL psilocin. Even at a supraclinical concentration of 60 ng/mL, the mean QTcF increase is 9.1 ms (upper limit 17.9 ms). Psilocin's short half-life (about 4 hours) suggests no accumulation with monthly oral dosing.
Translational Psychiatry
September 12, 2024
Christopher R. Nicholas, Matthew I Banks, Richard C Lennertz et al.
10 citations
Psilocybin, a serotonergic psychedelic, can relieve symptoms in several psychiatric disorders and improve well-being, but it was unclear whether these benefits arise during the acute experience or depend on later memory of it. In 8 healthy participants, psilocybin (25 mg) was co-administered with the amnestic benzodiazepine midazolam at a dose that allowed a conscious psychedelic experience while partially impairing memory for it. Higher midazolam doses and greater memory impairment tended to associate with lower salience, insight, and well-being from psilocybin. These results suggest memory plays a role in therapeutically relevant behavioral effects of psilocybin.
Psychedelic Medicine
December 1, 2023
Julia Malicki, Amelia Baltes, Christopher R. Nicholas et al.
7 citations
A clinical trial found that giving psilocybin together with buprenorphine to people with opioid use disorder was safely tolerated and did not interfere with buprenorphine's effectiveness or psilocybin's subjective effects. The study faced feasibility challenges that required changes to the participant pool and eligibility rules, along with strategies to improve accessibility, reduce burden, and increase generalizability.
bioRxiv (Cold Spring Harbor Laboratory)
June 13, 2024
Christopher R. Nicholas, Matthew I. Banks, Richard C Lennertz et al.
3 citations
preprint
Co-administering the amnestic benzodiazepine midazolam with psilocybin in 8 healthy participants partially impaired memory for the psychedelic experience while still allowing a conscious experience to occur. The degree of memory impairment was inversely associated with salience, insight, and well-being induced by psilocybin. These results suggest that memory of the acute psychedelic experience contributes to therapeutically relevant behavioral effects. Because midazolam blocks memory by blocking cortical neural plasticity, it may also help evaluate how the pro-neuroplastic properties of psychedelics contribute to their therapeutic activity.
JAMA Network Open
April 1, 2025
Paul R. Hutson
2 citations
No Summary
bioRxiv (Cold Spring Harbor Laboratory)
July 29, 2025
May Kung Sutherland, Christopher R. Nicholas, Richard C Lennertz et al.
preprint
Psilocybin, a serotonergic psychedelic, induces neural plasticity and alters consciousness, while midazolam, a benzodiazepine, blunts plasticity and causes sedation and amnesia. In an open-label pilot study, 25 mg of oral psilocybin was given alongside intravenous midazolam at doses that allowed a full psychedelic experience but reduced memory of it. EEG recordings showed that 15-30 minutes after dosing, when midazolam was at its target concentration, beta power increased and the spectral exponent decreased. As psilocybin's effects emerged over the next six hours, Lempel-Ziv complexity and spectral exponent increased while broadband power decreased. These findings suggest psilocybin's effects persist even with midazolam, supporting its use in mechanistic studies.
Translational Psychiatry
February 14, 2026
Michael H Sutherland, Christopher R. Nicholas, Richard C Lennertz et al.
Psilocybin, a serotonergic psychedelic, induces neural plasticity and alters consciousness, while midazolam, a benzodiazepine, blunts plasticity and induces sedation. In an open-label pilot study, 25 mg of oral psilocybin was given alongside intravenous midazolam at doses that allowed a full psychedelic experience but blunted memory. Electroencephalography (EEG) data showed that 15–30 minutes after dosing, when midazolam was at its target concentration, beta power increased and spectral exponent decreased. As psilocybin's effects emerged over the next six hours, Lempel-Ziv complexity and spectral exponent increased, while broadband power decreased, especially in delta, theta, and alpha bands. The findings suggest psilocybin's effects persist with midazolam, supporting its use in mechanistic studies.